Diabetes Ther (2016) 7:621–639 DOI 10.1007/s13300-016-0208-5

REVIEW

Strategies for Diabetes Management: Using Newer Oral Combination Therapies Early in the Disease Joel Zonszein . Per-Henrik Groop

Received: August 19, 2016 / Published online: October 31, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com

ABSTRACT

effectively as first-line therapy in combination with metformin, as well as in patients not

Introduction: The duration of uncontrolled type 2 diabetes mellitus (T2DM) can adversely

achieving therapy.

impact small and large vessels, eventually

Methods: For this review, a non-systematic

leading to microvascular and macrovascular complications. Failure of therapeutic lifestyle

literature search of PubMed, NCBI, and Google Scholar was conducted.

changes, monotherapy, and clinical inertia contribute to persistent hyperglycemia and

Results: New oral agents have made it possible to improve glycemic control to near-normal

disease progression. The aim was to review the

levels with a low risk of hypoglycemia and

complex pathophysiology of type 2 diabetes and how different oral agents can be used

without weight gain, and sometimes with weight loss. Early combination therapy is

Enhanced Content To view enhanced content for this article go to http://www.medengine.com/Redeem/ 0217F060488512AE. J. Zonszein (&) Montefiore Medical Center, University Hospital for Albert Einstein College of Medicine, Bronx, NY, USA e-mail: [email protected]

glycemic

goals

with

metformin

effective and has been shown to have a favorable legacy effect. A number of agents are available in a single-pill combination (SPC) that provides fewer pills and better adherence. Compared with adding a sulfonylurea, still the most common oral combination used, empagliflozin has been shown to decrease

P.-H. Groop Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

cardiovascular (CV) events in a dedicated CV

P.-H. Groop Folkha¨lsan Institute of Genetics, Folkha¨lsan Research Center, Biomedicum Helsinki, Helsinki, Finland

endpoints, whereas sulfonylureas have been associated with an increased risk of CV disease.

P.-H. Groop Baker IDI Heart & Diabetes Institute, Melbourne, Australia

outcome study, and pioglitazone has been effective in reducing the risk of secondary CV

In those failing metformin, triple oral therapy by adding a non-metformin SPC such as empagliflozin/linagliptin or pioglitazone/

Diabetes Ther (2016) 7:621–639

622

alogliptin is a good option for reducing glycated

periods of time (even years) before adding

hemoglobin (HbA1c) hypoglycemia.

additional therapy [4]. This step-up approach

without

significant

Conclusion: Clinicians have a comprehensive armamentarium of medications to treat patients with T2DM. Clinical evidence has shown that dual or triple oral combination therapy is effective for glycemic control, and early treatment is effective in getting patients to goal more quickly. Use of SPCs is an option for double or triple oral combination therapy and may result in better adherence.

glycemic control is often not durable [5, 6]. Several studies have stressed the importance of early treatment, not only to prevent small vessel disease complications, but to prevent cardiovascular (CV) events years after the completion of the trial (a result of the legacy effect) as well [7–9]. The

Keywords: DPP-4 inhibitors; Early combination therapy; Hyperglycemia; Hypoglycemia; Oral glucose-lowering agents; SGLT2 inhibitors; Single-pill Type 2 diabetes mellitus

is conducive to treatment failure; evidence from monotherapy studies shows that long-term

combination;

current therapeutic landscape also

results from caution based on potential adverse events with available glucose-lowering agents [4]. For example, insulins and sulfonylureas (SUs) are associated with weight gain and hypoglycemia [1], the latter being of particular concern in the elderly [10]. The management of T2DM may be facilitated with

INTRODUCTION

single-pill combinations (SPC) by enabling patients to take fewer pills per day, which may

Over the last several decades, the diabetes

lead to improved patient adherence [11]. Many combinations include metformin and can be

landscape improved

has

been transformed by understanding of

an its

used early in the disease. Two other SPCs,

pathophysiology and the development of an

pioglitazone/alogliptin and empagliflozin/ linagliptin, have shown good glucose-lowering

array of antihyperglycemic medications [1]. Yet, diabetes remains a pervasive disease with

efficacy when added to metformin [12, 13]. It is important to choose agents that treat the

immense public health consequences and increasing prevalence of type 2 diabetes

patient as a whole, not just their hyperglycemia.

mellitus (T2DM) in adults [2]. Despite the

For example, individuals with T2DM are at high risk of CV disease and need aggressive therapy

number of treatment options, hyperglycemia is still often poorly controlled [3], chiefly

that includes the management of concomitant CV risk factors such as obesity, hypertension,

reflecting the limitations inherent in treatment options for T2DM and clinical

and dyslipidemia [14]. In addition, patients

inertia. Lifestyle changes such as diet or

with T2DM and chronic kidney disease (CKD) are also at an increased risk of severe

exercise are insufficient, and the efficacy of pharmacologic agents is rarely sustained over

hypoglycemia [15] and present a treatment challenge. Metformin is not recommended for

time and may be limited by side effects. After prescribing therapeutic lifestyle changes, there

use in patients with an estimated glomerular

may be delays in initiating monotherapy, often

filtration rate (eGFR) less than 45 mL/min/ 1.732; however, metformin may be used safely

metformin, and physicians may wait long

in patients with mild impairment in kidney

Diabetes Ther (2016) 7:621–639

623

function and with proper monitoring in

empagliflozin.

patients with moderate impairment in kidney

identified after screening the titles, and results

function [16]. As the number of newly diagnosed patients with T2DM increases and

were then revised qualitatively on the basis of treatment initiation time and use of

patients live longer, CKD needs to be a consideration when choosing

combination or fixed-dose therapy. Relevant clinical trials evaluating early combination

antihyperglycemic

recently

therapy in patients with T2DM were identified

published long-term follow-up to the Steno-2 trial of patients with T2DM and

on ClinicalTrials.gov. Other sources included drug manufacturers’ websites and references

microalbuminuria, more intensified, multifactorial, target-driven treatment resulted

known to the author.

in an almost 8-year longer survival with fewer

Compliance with Ethics Guidelines

CV complications [17]. Thus, a one-size-fits-all approach to treat hyperglycemia is insufficient

This article is based on previously conducted

and a patient-centered approach is necessary. Herein, we describe the rationale for early

studies and does not involve any new studies of human or animal subjects performed by any of

combination

the authors.

agents.

therapy,

In

review

the

the

clinical

efficacy and safety data for the empagliflozin/ linagliptin SPC, and discuss how SPC therapy can be used in a personalized approach. This review discusses only oral agents as they are more commonly used early in the disease. Of the nine classes of oral medications listed in

Relevant

references

were

PATHOPHYSIOLOGY T2DM is a complex disease with multiple pathophysiologic

components

(Fig. 1).

Table 1, this paper focuses on the newer classes,

Elevated blood glucose results from insufficient insulin production and insulin

dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT-2)

resistance, as well as a closely intertwined dysfunction of many other metabolic and

inhibitors, available in the USA, as well as the older SUs and thiazolidinediones (TZDs), agents

hormonal

that are commonly prescribed when metformin

pathways

[18].

Impaired

b cell

function and impaired insulin secretion are hallmarks of T2DM. In addition, pancreatic

fails.

a cells secrete inappropriately high amounts of glucagon in spite of hyperglycemia and

REVIEW METHODS

hyperinsulinemia, the two major factors that

For this narrative review, a non-systematic

decrease glucagon secretion and endogenous glucose production. As a result, inappropriate

literature search was conducted on various databases, including PubMed, NCBI, and Google Scholar. The search terms included

endogenous glucose production leads to fasting hyperglycemia and also contributes to postprandial hyperglycemia.

type 2 diabetes, early treatment with oral agents such as linagliptin, empagliflozin,

T2DM has evolved into a disorder that now affects a younger population afflicted with

metformin, DPP-4 inhibitors, and fixed-dose combination with linagliptin and

central obesity and abnormal adipocyte function [19]. In addition, the gastrointestinal

Diabetes Ther (2016) 7:621–639

624

Table 1 Classes of oral medications for glycemic management approved in the USA [1, 24] Class

Compounds

Primary physiologic action

Hypoglycemia

Weight

Biguanides

Metformin

; Hepatic glucose production

Neutral

Slight loss

Sulfonylureas

Glyburide/glibenclamide

: Insulin secretion

Moderate/severe Gain

: Insulin secretion

Mild

Gain

: Insulin sensitivity

Neutral

Gain

Slows carbohydrate digestion/absorption

Neutral

Neutral

Neutral

Neutral

Neutral

Neutral

Neutral

Neutral

Glimepiride Glipizide Meglitinides

Repaglinide Nateglinide

Thiazolidinediones

Pioglitazone Rosiglitazone

a-Glucosidase inhibitors

Acarbose

DPP-4 inhibitors

Alogliptin

: Insulin secretion (glucose-dependent)

Linagliptin

; Glucagon secretion (glucose-dependent)

Miglitol

Sitagliptin Saxagliptin Bile acid sequestrants

Colesevelam

Dopamine-2 agonists

Bromocriptine (quick release)

; Hepatic glucose production (?) : Incretin levels (?) Modulates hypothalamic regulation of metabolism : Insulin sensitivity

SGLT2 inhibitors

Canagliflozin

Inhibit glucose reabsorption by the kidney Neutral

Dapagliflozin

: Glucosuria

Loss

Empagliflozin DPP-4 dipeptidyl peptidase-4, SGLT2 sodium glucose cotransporter 2

tract exhibits abnormal secretion of incretin

during fasting, and reabsorbing all of the

hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide

filtered glucose [21], both of which are adaptive mechanisms that ensure sufficient

[18, 20]. These two hormones account for 90%

energy is available during fasting periods. The

of the incretin effect, which plays a pivotal role in maintaining normal glucose homeostasis.

transport protein, SGLT2, is a low-affinity, high-capacity glucose transporter that

The kidneys also play a crucial role in glucose homeostasis by releasing glucose into the

reabsorbs approximately 90% of filtered glucose, while the high-affinity, low-capacity

circulation via gluconeogenesis, particularly

SGLT1 transporter reabsorbs the remainder [22].

Diabetes Ther (2016) 7:621–639

625

Fig. 1 Pathophysiologic abnormalities targeted by currently available antihyperglycemic medications. DPP4i dipeptidyl peptidase 4 inhibitor, GLP1 RA glucagon-like peptide 1 receptor agonist, HGP hepatic glucose production, MET metformin, SGLT2i sodium glucose cotransporter 2 inhibitor, TZD thiazolidinedione. ‘ From the

triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus’’. American Diabetes Association, 2009. Copyright and all rights reserved. Material from this publication has been used with the permission of the American Diabetes Association

A maladaptation takes place in individuals with diabetes with increased expression and activity

glucose dysregulation. In summary, complex and multiple pathophysiologic disturbances

of SGLT2 in the proximal tubule of the kidney.

involving different organs and endocrine and

As a result, glucose reabsorption increases by as much as 20% in individuals with poorly

neurologic pathways cause hyperglycemia, and therefore it is not surprising that a multitiered

controlled diabetes, contributing to hyperglycemia [22]. In T2DM and obesity, the

treatment approach is necessary.

central nervous system fuel feedback is affected

TREATMENT GUIDELINES AND APPROACHES

by insulin and leptin resistance, further contributing to glycemic dysregulation. Individuals with obesity and T2DM are insulin and leptin resistant and display neurotransmitter dysfunction that alters the normal fuel feedback to the brain [23], making the central nervous system a critical player in

Treatment

guidelines

developed

by

the

American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), as well as by the American Association of Clinical Endocrinologists (AACE) and the

Diabetes Ther (2016) 7:621–639

626

American College of Endocrinology (ACE), recommend

metformin

as

the

pharmacotherapy if lifestyle changes, such as diet and exercise, fail to achieve glycated hemoglobin (HbA1c) goals within 3 months [1, 24]. Metformin does not cause significant hypoglycemia, is weight neutral, inexpensive, and has a long-standing evidence base for efficacy and safety [1]; it may even reduce the risk of CV events [7]. On the basis of the Diabetes Prevention Program study, metformin is also recommended for individuals with prediabetes, particularly those with a body mass index greater than 35 kg/m2, aged less than 60 years, and women with previous gestational diabetes [25, 26]. If metformin is contraindicated (e.g., because of decreased renal function) or not tolerated, the AACE/ACE guidelines suggest the use of one of the newer agents, such as a GLP-1 receptor agonist, SGLT2 inhibitor, or DPP-4 inhibitor, over older agents (a-glucosidase inhibitors, TZDs, and SUs) [24]. The ADA/EASD Position Statement does not prioritize treatments and instead emphasizes patient preference and individualized treatment [1]. Individuals with T2DM benefit from learning adopting

DPP-4 Inhibitors

first-choice

about managing their disease, a healthier lifestyle, and

understanding the pros and cons of their medications. Well-structured education, such as diabetes self-management education, should

DPP-4 inhibitors are gastrointestinal peptides that enhance secretion of insulin from pancreatic b cells and suppress glucagon release from pancreatic a cells glucose-dependent manner [29].

in a DPP-4

inhibitors have a low risk of hypoglycemia, are weight neutral, have been shown to improve b cell function in animal and in vitro studies [30, 31], and can exert several favorable effects on the CV system, including improved ventricular

function

[32].

Currently,

four

DPP-4 inhibitors are approved in the USA for the treatment of hyperglycemia alone or in combination with other oral agents and insulin: alogliptin, linagliptin, sitagliptin, and saxagliptin (Table 2). In clinical trials, DPP-4 inhibitor monotherapy has been shown to improve glycemic control with mean reductions in HbA1c in the range of 0.6–1.1% [33]. When used in patients with moderate or severe

CKD,

alogliptin,

saxagliptin,

and

sitagliptin require a lower dose [34]. Linagliptin, the only DPP-4 inhibitor primarily excreted via the hepatic route, does not require any dose adjustment. All DPP-4 inhibitors are well tolerated, but have been associated with an increased frequency of stuffy nose or cough [35] and some cases of severe and disabling arthralgia have been reported more recently [36]. Reports of pancreatitis and pancreatic

aim to support informed decision-making, problem-solving, and active collaboration with

cancer with the use of incretinomimetics are

the health care team to improve clinical

still under investigation [37].

outcomes, health status, and quality of life in a cost-effective manner [27, 28]. Monitoring

SGLT2 Inhibitors

glycemic goals via determination of HbA1c levels and self-monitoring of blood glucose (SMBG) varies according to the individual and

SGLT2 inhibitors exert their effects via the kidney and their mechanism of action

his or her treatment [1].

involves inhibiting the SGLT2 protein in the

2.5/1000 XR–5/1000 XR 2.5/1000 XR–5/500 XR–5/1000 XR

JentaduetoÒ XR (Boehringer Ingelheim Pharmaceuticals, Inc.) KombiglyzeÒ XR (AstraZeneca Pharmaceuticals, LP)

Linagliptin ? metformin XR

Saxagliptin ? metformin XR

DPP-4 inhibitor ? TZD

Combinations without metformin

Glyburide ? metformin

SU ? metformin Generic

2.5/500–5/500

Twice daily

Twice daily

2/500–4/500–2/10–4/1000

AvandametÒ (GlaxoSmithKline)

Rosiglitazone ? metformin

Twice daily Once daily

15/500–15/850

Actoplus Met XR (Takeda Pharmaceuticals America, Inc.) 15/1000–30/1000

Ò

Actoplus MetÒ (Takeda Pharmaceuticals America, Inc.)

Pioglitazone ? metformin XR

Pioglitazone ? metformin

TZD ? metformin

5/500 –5/1000 – 12.5/500 – 12.5/1000

SynjardyÒ (Boehringer Ingelheim Pharmaceuticals, Inc.)

Empagliflozin ? metformin

Twice daily

5/500 XR–5/1000 XR–10/500 XR–10/1000 Once daily XR

XigduoÒ XR (AstraZeneca Pharmaceuticals, LP)

Dapagliflozin ? metformin XR

Twice daily

50/500 XR–50/1000 XR–150/500 XR–150/ Once daily 1000 XR

50/500–50/1000–150/500–150/1000

Invokamet XR (Janssen Pharmaceuticals, Inc.)

Ò

Once daily

Twice daily

Once daily

Once daily

Twice daily

Twice daily

Administration

Canagliflozin ? metformin XR

Canagliflozin ? metformin

InvokametÒ (Janssen Pharmaceuticals, Inc.)

50/500 XR–50/1000 XR–100/1000 XR

JanumetÒ XR (Merck Sharp & Dohme Corp.)

Sitagliptin ? metformin XR

SGLT2 inhibitor ? metformin

50/500–50/1000

Janumet (Merck Sharp & Dohme Corp.)

Sitagliptin ? metformin

Ò

2.5/500–2.5/850–2.5/1000

12.5/500–12.5/1000

Jentadueto (Boehringer Ingelheim Pharmaceuticals, Inc.)

Ò

KazanoÒ (Takeda Pharmaceuticals America, Inc.)

Dosages, mg/mg

Linagliptin ? metformin

Alogliptin ? metformin

DPP-4 inhibitor ? metformin

Combinations with metformin

Brand name

Table 2 SPC therapies available for T2DM in the USA

Diabetes Ther (2016) 7:621–639 627

Diabetes Ther (2016) 7:621–639

Please consult full prescribing information for contraindications, warnings and precautions, and dosage and administration for use in specific populations (e.g., renal impairment) DPP-4 dipeptidyl peptidase 4, SGLT2 sodium glucose cotransporter 2, SU sulfonylurea, T2DM type 2 diabetes mellitus, TZD thiazolidinedione, XR extended release

Once daily 4/1–4/2–4/4–8/2–8/4 Generic Rosiglitazone ? glimepiride

Once daily Pioglitazone ? glimepiride

TZD ? SU

DuetactÒ (Takeda Pharmaceuticals America, Inc.)

GlyxambiÒ (Boehringer Ingelheim Pharmaceuticals, Inc.) Empagliflozin ? linagliptin

SGLT2 inhibitor ? DPP-4 inhibitor

10/5–25/5

30/2–30/4

Once daily

Once daily 12.5/15–12.5/30–12.5/45–25/15–25/ 30–25/45 OseniÒ (Takeda Pharmaceuticals America, Inc.) Alogliptin ? pioglitazone

Table 2 continued

Brand name

Dosages, mg/mg

Administration

628

proximal

nephron,

thereby

reducing

the

inappropriately increased glucose reabsorption found in T2DM and increasing urinary glucose excretion [38]. SGLT2 inhibitors have proven to be effective not only in improving glycemic management but also in decreasing weight and reducing systolic blood pressure (BP), with a low risk of hypoglycemia, except when used with insulin or SUs [38]. They provide significant reductions in HbA1c versus placebo and are similarly efficacious when compared with most standard oral agents in head-to-head trials [39]. Because this action is independent of insulin, SGLT2 inhibitors may be used at any stage of T2DM, even after insulin secretion has waned significantly [38]. The SGLT2 inhibitors lead to increased risk of genital mycotic infections, particularly in women. Urinary tract infections have also been reported to be more common in some patient groups, such as older patients, but the increase is less clear-cut than for genital infections [40]. Use of SGLT2 inhibitors also has the potential to cause hypotension and other hypovolemic events because of osmotic diuresis, particularly in older patients taking loop diuretics. In addition, trials have shown small increases in low-density lipoprotein cholesterol

and,

although

these

can

be

managed with appropriate treatment, the long-term consequences are unclear. Long-term trials to establish CV safety are still ongoing for canagliflozin and dapagliflozin

[41].

Results

from

the

Ò

EMPA-REG OUTCOME trial showed a significant CV risk reduction [42], decreased CV and overall mortality, slower progression of kidney disease, and lower rates of clinically relevant renal events in patients with T2DM and CV risk factors who were treated with empagliflozin versus placebo in addition to standard of care [43] (see ‘‘CV Risk’’ section).

Diabetes Ther (2016) 7:621–639

629

Post-marketing reports of ketoacidosis have

Cardiovascular Outcomes and Regulation of

emerged after the approval of SGLT2 inhibitors,

Glycaemia in Diabetes (RECORD), compared

with a number of cases reporting minimal elevation of blood sugar (i.e., euglycemic

metformin plus SU with metformin plus rosiglitazone, and also found better glycemic

ketoacidosis) [44]. The US Food and Drug Administration (FDA) has subsequently issued

control with the combination of rosiglitazone and metformin [48]. Since these are the only

a warning alerting health care practitioners and

two

patients to the ketoacidosis [45].

available, treatment decisions should be patient-centered and include considerations

signs

and

symptoms

of

long-term

randomized

clinical

trials

such as efficacy, cost, potential side effects, weight, comorbidities, hypoglycemia risk, and

Combination Therapy

patient preferences [25]. Current guidelines recommend combination therapy in patients with elevated HbA1c levels

Although many shorter-term trials have compared dual therapy versus metformin

at diagnosis (ADA/EASD[9.0%; AACE/ ACE C7.5%) or after 3 months of monotherapy

monotherapy, few long-term, head-to-head studies have directly compared drugs as

if HbA1c goals are not achieved [1, 24]. To address the lack of long-term studies assessing

add-on therapy. A comparative effectiveness

the efficacy and safety of initial combination

meta-analysis suggests that, overall, each new class of non-insulin agents added to initial

therapy, the US National Institutes of Health has sponsored the Glycemia Reduction

therapy lowers HbA1c levels by approximately 1% [49]. These differences may be true in

Approaches in Diabetes: A Comparative Effectiveness (GRADE) study [46]. The trial

clinical trials, however, in day-to-day practice tremendous variability occurs among patients’

does not compare older combinations, such as TZDs, or newer agents, such as the SGLT2

responses to medications.

inhibitors, and is limited to comparing the combination of metformin with DPP-4 inhibitors, GLP-1 receptor agonists, insulin, or

CV RISK

SUs. Until the GRADE trial is completed (estimated 2020), only two randomized,

Intensive Glucose Lowering

controlled, long-term studies (both 5 years) are

CV disease is the major cause of morbidity and premature mortality and an important

available. First, Revascularization

the Bypass Investigation

Angioplasty 2 Diabetes

contributor to the direct and indirect costs of

different (mainly

diabetes [50]. Benefits can be seen when multiple risk factors (e.g., BP, weight, smoking cessation)

insulin and SUs) versus insulin sensitizers

are addressed globally [51, 52]. Long-term clinical trials have also shown that aggressive glycemic

(BARI 2D) study compared two strategies, insulin secretagogues

(mainly metformin and rosiglitazone). The study showed that the insulin sensitizer

treatment benefits CV outcomes years after the

strategy not only achieved better glycemic control but was also associated with less

studies have been completed [7–9, 52]. These effects have been clearly demonstrated in patients

hypoglycemia and less weight gain [47]. The

with type 1 diabetes mellitus (T1DM) in the Diabetes Control and Complications Trial/

second

trial,

Rosiglitazone

Evaluated

for

Diabetes Ther (2016) 7:621–639

630

Epidemiology of Diabetes Interventions and

Several CV outcomes trials have compared

Complications study (DCCT/EDIC) [53]. This

DPP-4 inhibitors with placebo or other agents in

was also shown in patients with T2DM in the UK Prospective Diabetes Study (UKPDS) [7], and more

addition to the usual standard of care for glycemic control and CV risk factors [62–64].

recently in the long-term follow-up of the Veterans Affairs Diabetes Trial (VADT) in which

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes

CV disease improvement was found 10 years after

Mellitus–Thrombolysis in Myocardial Infarction

the study end [8], the legacy effect [7]. Although the Action to Control Cardiovascular Risk in

(SAVOR-TIMI) 53 trial, which compared saxagliptin versus placebo in T2DM patients

Diabetes (ACCORD) study found that intensive therapy (targeting HbA1c\6.0%) in patients with

with either a history of established CV events or at high risk of CV events (N = 16,492) over a

T2DM

with

median of 2.1 years, the rates of the composite

standard therapy (targeting HbA1c 7.0–7.9%) [54], the VADT and the Action in Diabetes and

primary endpoint [CV death, nonfatal myocardial infarction (MI), or ischemic stroke]

Vascular Disease (ADVANCE) trials showed that intensive glucose control did not increase

were similar between the treatment groups [hazard ratio (HR), 1.00; 95% confidence

mortality [55, 56]. VADT showed a reduction in

interval

CV event rates years after the study was completed (median follow-up, 5.6 years) [8]. However,

non-inferiority; P = 0.99 for superiority] [62]. However, saxagliptin showed a higher rate of

interventions at a later disease stage, such as intensive treatment in those with heart and

hospitalization due to heart failure (3.5%) relative to placebo (2.8%; HR, 1.27; 95% CI,

kidney disease, can also produce a legacy effect after aggressive multifactorial treatment

1.07–1.51; P = 0.007) [62]. In the Examination of Cardiovascular Outcomes with Alogliptin

initiation. A recent follow-up to the Steno-2

versus Standard of Care (EXAMINE) trial,

trial, following patients for a mean of 21.2 years after 7.8 years of intensified multifactorial

which investigated alogliptin versus placebo in patients with acute coronary syndrome over a

treatment in patients with T2DM and microalbuminuria, demonstrated a median gain

median of 1.5 years, alogliptin was non-inferior to placebo for the primary composite endpoint

of 7.9 life-years [17].

(CV death, nonfatal MI, or nonfatal stroke): HR,

When metformin is not indicated or tolerated, including in treatment-naı¨ve

0.96; upper boundary of the one-sided repeated CI, 1.16; P\0.001 for non-inferiority; P = 0.32

individuals, the empagliflozin/linagliptin SPC can be a good alternative. Although the

for superiority [63]. Moreover, in a post hoc analysis, the first hospitalization due to heart

addition of an SU is the most common step

failure occurred at similar rates in both

after metformin fails, these agents have been associated with hypoglycemia, sometimes

treatment groups (alogliptin, 3.1%, placebo, 2.9%; HR, 1.07; 95% CI, 0.79–1.46; P = 0.657)

requiring hospitalizations, particularly in the elderly [10] and in those with polypharmacy

[64]. The larger (N = 14,671) and longer (median follow-up, 3.0 years) Trial Evaluating

increased

mortality

compared

(CI),

0.89–1.12;

P\0.001

for

[57]. Observational cohort trials have also

Cardiovascular

shown a disadvantage of SUs in general [58, 59], and when compared to DPP-4

(TECOS) trial evaluated sitagliptin versus placebo on top of usual care in patients at

inhibitors [60, 61].

least 50 years of age with T2DM and established

Outcomes

with

Sitagliptin

Diabetes Ther (2016) 7:621–639

631

reassuringly

heart failure (HR, 0.65; 95% CI, 0.50–0.85;

demonstrated no increased risk versus placebo

P = 0.002), and death from any cause (HR,

for the primary composite CV endpoint of CV death, nonfatal MI, nonfatal stroke, or

0.68; 95% CI, 0.57–0.82; P\0.001). Among patients receiving empagliflozin, there was an

hospitalization for unstable angina (alogliptin, 9.6%, placebo, 9.6%; HR, 0.98; 95% CI,

increased rate of genital infection but no increase in other adverse events.

CV

disease

[65].

The

results

0.88–1.09; P\0.001 for non-inferiority in the per-protocol population; P = 0.65 for superiority) and no increase in hospitalization

CV Outcomes Trials with TZDs

for heart failure [HR in the intent-to-treat analysis: 1.00 (95% CI, 0.83–1.20); P = 0.98]

The TZDs are among the most potent insulin-sensitizing drugs available. Their use in

[65].

patients with T2DM has decreased mainly as a result of the adverse CV outcomes attributed to

CV Outcomes Trials with SGLT2 Inhibitors

rosiglitazone [68]. Pioglitazone, the other agent

Ongoing clinical trials assessing the impact of

in this class, may reduce the risk of CV events, including stroke [69]. The PROspective

the SGLT2 inhibitors dapagliflozin and canagliflozin in patients with T2DM at high

PioglitAzone Clinical Trial In macro-Vascular Events (PROactive) trial evaluated the addition

risk of CV complications include Dapagliflozin

of pioglitazone to current therapy in patients

Effect on CardiovascuLAR Events (DECLARE-TIMI 58) [41] and CANagliflozin

with T2DM and a history of macrovascular disease (N = 5238). Although the trial failed to

cardioVascular Assessment Study (CANVAS) [66, 67]. For empagliflozin, the recently

meet its primary composite endpoint of death from any cause, nonfatal MI, stroke, acute

completed EMPA-REG OUTCOMEÒ trial is the first dedicated CV outcome study to demonstrate

coronary syndrome, leg amputation, coronary revascularization, or revascularization of the

that a glucose-lowering agent can improve CV

leg, a significant reduction in the composite

endpoints and lower CV mortality as well as all-cause mortality in patients with T2DM at

secondary endpoint was observed (death from any cause, nonfatal MI, or nonfatal stroke: HR

high risk of CV events [42]. It evaluated the effects of empagliflozin (10 or 25 mg once daily

0.84; 95% CI, 0.72–0.98; P = 0.027) [70]. In a follow-up analysis, the pioglitazone reduced

versus placebo) on top of standard of care on CV

rates of fatal or nonfatal stroke and the

outcomes in 7020 patients with T2DM at high risk of CV disease. The primary outcome was a

composite of CV death, nonfatal stroke, or MI among patients with a history of previous stroke

composite of death from CV causes, nonfatal MI, or nonfatal stroke (3-point major adverse

[69]. More recently, pioglitazone was also found to lower the risk of stroke or MI in individuals

cardiovascular

was

without diabetes who had insulin resistance

significantly reduced with empagliflozin (HR, 0.86, 95% CI, 0.74–0.99; P\0.001 for

along with ischemic stroke or transient ischemic attacks [71]. Although pioglitazone

non-inferiority and P = 0.04 for superiority). Empagliflozin resulted in significantly lower

has shown beneficial CV outcomes, other studies with the long-term use of TZDs,

rates of death from CV causes (HR, 0.62; 95%

mainly rosiglitazone [48, 72], have shown no

CI, 0.49–0.77; P\0.001), hospitalization for

superiority.

events

or

MACE)

and

Diabetes Ther (2016) 7:621–639

632

SPC THERAPY

antihyperglycemic SPCs are easy to tolerate, easy to prescribe, require little or no dose

Individuals with T2DM are often exposed to polypharmacy, not only because of the need for multiple antihyperglycemic agents but also because of additional medications for the treatment of hypertension,

CV risk factors, including dyslipidemia, and other

comorbidities [73]. In the Diabetes and Aging Study, which analyzed data from more than 46,000 patients with T2DM in the USA, the mean number of prescribed medications was 4.2, with 14% of patients taking more than seven medications [74]. Similarly large numbers of medications were used by patients in the UKPDS 35 prospective observational study and the BARI 2D trials [47, 75]. Given the substantial polypharmacy, strategies to improve adherence are welcome in T2DM. As such, treatment with an SPC can facilitate medication adherence,

titration, are associated with a low risk of hypoglycemia, and therefore need less frequent blood glucose monitoring. Efficacy is generally comparable between SPCs and separate-pill combination therapy [84]. Although randomized controlled studies of SPCs are limited, most studies demonstrate improved or equivalent efficacy of the SPCs compared with the monotherapies [83]. Pharmacokinetic studies have demonstrated bioequivalence for several SPCs with their corresponding loose-pill regimens, including those with metformin extended release (XR) [e.g., Actoplus MetÒ XR (Takeda Pharmaceuticals America, Inc.), KombiglyzeÒ XR (AstraZeneca Pharmaceuticals, LP), and JanumetÒ XR (Merck Sharp & Dohme Corp.)]

with the goal of improving health outcomes.

[83]. Metformin, the most commonly found agent in the SPC therapies currently available in

Using SPCs simplifies the treatment regimen by decreasing the number of pills and reducing

the USA, is effective in reducing blood glucose levels, but some patients have difficulty

the frequency of administration. Studies show that adherence is improved with administration

tolerating

this

agent

because

of

adverse

of one tablet per day versus multiple tablets per

gastrointestinal effects [85]. Despite these adverse effects, metformin remains the most

day [76–81]. Greater improvements in glycemic control have also been shown with an SPC

commonly prescribed medication, both in monotherapy and combination [86]. SPCs are

versus the same medications coadministered as separate pills [77]. However, data directly

particularly useful when they can be taken once

addressing the effects of antihyperglycemic

daily, and there are many fixed-dose combinations containing metformin XR

SPCs with respect to health care costs are quite limited [82]. Some data suggest reduced health

(Table 2), which also improves gastrointestinal tolerability [83]. One pill a day facilitates

care utilization and costs with an SPC versus loose-pill regimens [11]—a paradox as many

adherence [76].

formularies penalize SPCs with higher prices.

As with metformin, SUs have also been used extensively in SPC therapies, partly because

Prescribing an SPC limits dose flexibility, and thus many physicians prefer using them as a

they have been available for many years and partly because they are generic and thus

maintenance option rather than an initial therapy. However, the SPCs currently available

relatively inexpensive. The initial SPC was a

for use in T2DM are formulated in a variety of

combination of metformin and an SU. It was followed by an SU combined with a TZD, now

dosage combinations [83] (Table 2). Modern

also available in a generic form (Table 2). These

Diabetes Ther (2016) 7:621–639

633

SPCs may be less frequently prescribed because

24 weeks

they are associated with the disadvantages of

25 mg/linagliptin

was

higher

with

SUs; namely, lack of glycemic durability, hypoglycemia, and weight gain [25]. The third

empagliflozin 10 mg/linagliptin 5 mg (62.3%) versus empagliflozin alone (25 mg, 41.5%;

type of SPC therapy contains neither metformin nor an SU; these agents can be added to

10 mg, 38.8%) or linagliptin alone (5 mg, 32.3%) [88]. In this trial, however, the

metformin when metformin alone is no longer

empagliflozin 25 mg/linagliptin 5 mg SPC was

sufficient. There are only two such SPCs approved by the US FDA: pioglitazone/

not significantly better than empagliflozin 25 mg alone. When compared with linagliptin

alogliptin [OseniÒ (Takeda Pharmaceuticals America, Inc.)] and empagliflozin/linagliptin

5 mg alone, both SPC doses significantly reduced HbA1c, suggesting that without

[GlyxambiÒ

5 mg

empagliflozin (55.4%)

and

Ingelheim

metformin the glucose reduction is mostly

Pharmaceuticals, Inc.)] [87]. The combination of dapagliflozin/saxagliptin was submitted for

driven by empagliflozin [88]. Body weight reductions with the SPCs were also similar to

FDA review, and the FDA has asked for additional data.

empagliflozin alone, as were systolic BP reductions from baseline (2.1–2.5 mmHg) and

(Boehringer

a low incidence of hypoglycemia. Empagliflozin/Linagliptin SPC

In both of these trials, events consistent with urinary tract infections occurred at comparable

When treatment with metformin alone is not sufficient, the empagliflozin/linagliptin SPC can

rates across all groups (10–16%), and events consistent with genital infection were present

provide better HbA1c reductions than empagliflozin or linagliptin alone. In a

in 2–8.5% of patients, mostly women. In summary, the empagliflozin/linagliptin SPC is

placebo-controlled study (n = 674), 61.8% and 57.8% of patients with baseline HbA1c of at

well tolerated, may cause a modest weight loss

least 7.0% achieved an HbA1c of less than 7.0%

with lower systolic BP, and has a low rate of hypoglycemia.

at week 24 with empagliflozin 25 mg/linagliptin 5 mg and empagliflozin 10 mg/linagliptin 5 mg,

Pioglitazone/Alogliptin SPC

respectively, versus 28.0–36.1% of patients who were using any of the three agents alone [13]. Even greater HbA1c reductions were achieved in

Another available SPC is pioglitazone plus alogliptin. In drug-naı¨ve patients, the

individuals with a baseline HbA1c of at least 8.5%, and these improvements in glycemic

combination with pioglitazone 30 mg/ alogliptin 25 mg resulted in greater reductions

control were associated with weight loss and reduced systolic BP [13].

in HbA1c (-1.7 ± 0.1% from an 8.8% mean baseline) versus pioglitazone 30 mg

The empagliflozin/linagliptin SPC may be a

(-1.2 ± 0.1%, P\0.001) or alogliptin 25 mg

good alternative when metformin is not indicated or tolerated or in treatment-naı¨ve individuals. In treatment-naı¨ve patients with

(-1.0 ± 0.1%, P\0.001) alone [89]. When added to metformin, the pioglitazone/

T2DM and moderate hyperglycemia (n = 677;

alogliptin SPC was also well tolerated and effective [12]. When administered to

mean HbA1c, 8.0%), the proportion who

individuals with HbA1c 7.5–10.0% receiving at

achieved HbA1c levels less than 7.0% at

least 1500 mg/day of metformin, pioglitazone

Diabetes Ther (2016) 7:621–639

634

plus metformin (pooled group) achieved a

Several CV outcomes trials have been

mean HbA1c reduction from baseline of 0.9%.

completed for the individual glucose-lowering

In contrast, participants receiving triple therapy (alogliptin, pioglitazone, and metformin)

agents. CV outcomes trials for sitagliptin, saxagliptin, and alogliptin have shown no

achieved a mean HbA1c reduction of 1.4% (P\0.001 versus the pioglitazone plus

increased risk of overall CV events. EMPA-REG OUTCOME is the only trial that has

metformin pooled group).

demonstrated that adding empagliflozin causes a reduction in major adverse CV events, all-cause mortality, CV mortality, and heart

CONCLUSIONS Antihyperglycemic SPCs have been developed in an effort to address the issues of adherence

failure, as well as an improvement in renal outcomes, when compared to treatment placebo on top of the current recommended

associated with combination pharmacotherapy for patients with T2DM, with the goal of

standard of care [42, 43]. In a post hoc analysis pioglitazone has also been found to have

optimizing

favorable CV outcomes when used for secondary intervention when compared to

clinical

outcomes.

Most

SPCs

contain metformin or an SU. On the basis of current guidelines, metformin is the preferred

placebo [69, 70]. In summary, we now have

choice for one of the agents in combination therapy. The use of SUs is less desirable because

different choices in the selection of oral agents available for management of hyperglycemia.

of weight gain, hypoglycemia, and potential CV

While the treatment choice needs to be patient-centered, we now have medications

risks. When considering orally administered alternatives or additions to metformin therapy, agents with a low risk of hypoglycemia that provide weight neutrality or weight loss and have a proven CV safety profile are preferred. In the USA,

two

combinations are alogliptin/pioglitazone and empagliflozin.

Both

non-metformin available, linagliptin/

combinations

contain

DPP-4 inhibitors, which are associated with weight neutrality. However, when used in combination, linagliptin/empagliflozin is associated with weight loss due to the SGLT2 component,

and

alogliptin/pioglitazone

is

associated with weight gain due to the TZD component. These combinations are associated with a low risk of hypoglycemia (except when used in conjunction with insulin or insulin secretagogues). Neither combination has been studied in a dedicated CV outcomes trial.

that in addition to glycemic control also reduce CV outcomes. Early diagnosis of T2DM and aggressive glycemic treatment may help preserve b cell function. In addition, clinical studies suggest that aggressive and early glycemic therapy reduces complications, and the use of lifestyle changes together with initial combination therapy is recommended. Clinicians now have a choice of what to use initially with metformin, or what to add when metformin fails. Newer combinations are weight neutral or may provide weight loss. Adding an SPC may improve adherence by decreasing the number of pills needed. Finally, the cost of expensive newer medications must be measured along with the potential costs of complications associated

with

older

medications.

For

example, sulfonylureas are associated with hypoglycemia, and medical interventions for

Diabetes Ther (2016) 7:621–639

635

hypoglycemia often require more monitoring

Pharmaceuticals North America, Inc, Sanofi,

and sometimes costly hospitalizations [90].

and Boehringer Ingelheim. P-H Per-Henrik Groop has received

In managing diabetes, early diagnosis and treatment with better lifestyles and proper

honoraria

from

AstraZeneca,

Groop lecture

Boehringer

medications can normalize HbA1c without hypoglycemia and/or weight gain. The use of

Ingelheim, Eli Lilly, Genzyme, MSD, Novartis, Novo Nordisk; has received

SPC

investigator-initiated grants from Eli Lilly and Roche; and is a member of advisory boards for

therapy

is

recommended

for

better

adherence, and a more aggressive early treatment should result in fewer complications and a better quality of life. Consideration is needed in every case to provide a

AbbVie, Boehringer Ingelheim, Cebix, Eli Lilly, Janssen, Medscape, MSD, Novartis, and Sanofi.

the

Compliance with Ethics Guidelines. This

patient as a whole. This necessarily includes taking into account concomitant risk factors

article is based on previously conducted studies and does not involve any new studies

such as obesity, hypertension, dyslipidemia, and renal impairment, as well as addressing

of human or animal subjects performed by any

patient-centered

approach

that

treats

of the authors.

medication risk–benefit profiles and costs, when making treatment choices.

Open Access. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License

ACKNOWLEDGEMENTS

(http://creativecommons.org/licenses/

No funding or sponsorship was received for this

by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any

study or publication of this article. Editorial support for this manuscript was provided by

medium, provided you give appropriate credit to the original author(s) and the source, provide

Linda Merkel, PhD, of Envision Scientific

a link to the Creative Commons license, and

Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc.

indicate if changes were made.

(BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy

as

well

as

intellectual

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Strategies for Diabetes Management: Using Newer Oral Combination Therapies Early in the Disease.

The duration of uncontrolled type 2 diabetes mellitus (T2DM) can adversely impact small and large vessels, eventually leading to microvascular and mac...
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